ASSOCIATION OF MINISATELLITE INSTABILITY WITH C-MYC AMPLIFICATION ANDK-RAS MUTATION IN METHYLCHOLANTHRENE-INDUCED MOUSE SARCOMAS

Instability of microsatellite sequences are frequently found in human tumors. In addition, minisatellite sequences, another group of highly unstable sequences, serve as sensitive markers of genetic instability. We have studied minisatellite instability in methylcholanthrene-induc ed mouse sarcomas. These sarcomas frequently carry the amplified c-myc gene. Seven sarcomas without the amplification and seven others with the amplification were selected randomly. Regardless of the state of t he c-myc gene amplification, these sarcomas exhibited a varying degree of transplantability in syngeneic mice. The hypervariable mouse minis atellite locus Ms6hm was found to be highly unstable, specifically amo ng sarcomas with the amplified c-myc gene. However, chromosome instabi lity, as analyzed by micronucleus assay, was observed similarly for tw o groups of sarcomas. In addition, transversion of G to C and A to T w as detected at the K-ras gene in four of the seven sarcomas with the a mplified c-myc gene, and these mutations are thought to be induced dir ectly by methylcholanthrene. Thus, concomitant occurrence was observed for three seemingly unrelated mutations, amplification of the c-myc l ocus, point mutation of the K-ras gene, and instability at the hyperva riable mouse minisatellite locus. The present study indicates a possib le involvement of K-ras mutation and c-myc amplification in induction of genetic instability in methylcholanthrene-induced mouse sarcomas.